Ivermectin Inhibits Stress Granule Clearance by Blocking the De Novo Synthesis of Hsp70 in Neuroblastoma Cells.

Cytoplasmic stress granules (SGs) form in response to diverse insults; they are dismantled when the stress subsides. SG clearance is facilitated by molecular chaperones, nuclear transport factors, and other components. The anti-parasitic drug ivermectin inhibits nuclear trafficking and has potential anti-cancer activities. However, the molecular pathways that promote ivermectin's therapeutic actions are poorly understood. Our study defined the effects of ivermectin on stress recovery in human neuroblastoma and cervical carcinoma cells. We demonstrate that ivermectin interferes with SG disassembly in neuroblastoma cells. The delay of SG dissolution is accompanied by significant changes in the proteostasis network. Notably, ivermectin diminishes de novo protein synthesis in unstressed and stressed cells. During recovery, ivermectin reduces the abundance of hsp70 in neuroblastoma, but not in cervical carcinoma cells. Surprisingly, ivermectin has no effect on Hsf1 abundance and localization. Moreover, ivermectin does not diminish the levels of transcripts encoding hsp70. Bioorthogonal Non-Canonical Amino Acid Tagging revealed that ivermectin markedly reduces the stress-induced de novo synthesis of hsp70 in neuroblastoma cells. Taken together, ivermectin can derail stress responses by a unique mechanism that alters the translation of hsp70 mRNA and is determined by the cellular context. This information is directly relevant to ivermectin-based anti-cancer therapies.